MX2007010991A

MX2007010991A - Potassium channel modulating agents and their medical use.

Info

Publication number: MX2007010991A
Application number: MX2007010991A
Authority: MX
Inventors: Lene Teuber; Birgitte L Eriksen; Ulrik Svane Soerensen; Charlotte Hougaard
Original assignee: Neurosearch As
Priority date: 2005-03-14
Filing date: 2006-03-13
Publication date: 2007-11-07
Also published as: AU2006224605B2; EP1861388B1; US8252806B2; AU2006224605A1; WO2006097441A1; US20080275045A1; JP4966958B2; EP1861388A1; JP2008533087A; CA2601527A1; NZ556248A

Abstract

This invention relates to novel potassium channel modulating agents, and their use in the preparation of pharmaceutical compositions. Moreover the invention is directed to pharmaceutical compositions useful for the treatment or alleviation of diseases or disorders associated with the activity of potassium channels, in particular respiratory diseases, epilepsy, convulsions, vascular spasms, coronary artery spasms, renal disorders, polycystic kidney disease, bladder spasms, urinary incontinence, bladder outflow obstruction, irritable bowel syndrome, gastrointestinal dysfunction, secretory diarrhoea, ischaemia, cerebral ischaemia, ischaemic heart disease, angina pectoris, coronary heart disease, traumatic brain injury, psychosis, schizophrenia, anxiety, depression, dementia, memory and attention deficits, Alzheimer's disease, dysmenorrhea, narcolepsy, Reynaud's disease, intermittent claudication, Sjorgren's syndrome, migraine, arrhythmia, hypertension, absence seizures, myotonic muscle dystrophia, xerostomi, diabetes type II, hyperinsulinemia, premature labour, baldness, cancer, immune suppression or pain.

Description

AGENTS THAT MODULATE THE POTASSIUM CHANNEL AND ITS MEDICAL USE FIELD OF THE INVENTION This invention relates to new agents that modulate the potassium channel, and its use in the preparation of pharmaceutical compositions. In addition, the invention is directed to pharmaceutical compositions useful for the treatment or alleviation of diseases or disorders associated with the activity of potassium channels, in particular, respiratory diseases, epilepsy, seizures, seizures, absence attacks, vascular spasms, artery spasms. coronary, renal disorders, polycystic kidney disease, bladder spasms, urinary incontinence, bladder flow obstruction, erectile dysfunction, gastrointestinal dysfunction, secretory diarrhea, ischemia, cerebral ischemia, ischemic heart disease, angina pectoris, coronary heart disease, ataxia, traumatic brain injury, Parkinson's disease, bipolar disorder, psychosis, schizophrenia, anxiety, depression, mood disorders, dementia, attention deficit and memory, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), dysmenorrhea, narcolepsy, Reynaud's disease, intermittent claudication, Sjorgren's syndrome, arr itmia, hypertension, myotonic muscular dystrophy, spasticity, xerostomia, type II diabetes, hyperinsulinemia, premature labor, baldness, REF. : 183421 cancer, irritable bowel syndrome, immune suppression, migraine or pain.

BACKGROUND OF THE INVENTION Ion channels are transmembrane proteins, which catalyze the transport of inorganic ions through cell membranes. Ionic channels participate in processes as diverse as the generation and programming of action potentials, synaptic transmissions, hormone secretion, muscle contraction, etc. All mammalian cells express potassium (K +) channels in their cell membranes, and channels play a dominant role in regulating membrane potential. In nerve and muscle cells, they regulate the frequency and shape of the action potential, the release of neurotransmitters, and the degree of bronchodilation and vasodilation. From a molecular point of view, the K + channels represent the broadest and most diverse group of ion channels. For an overview, they can be divided into five large families: K + channels activated with voltage (Kv), K + channels related to QT (KvLQT), rectifiers inwards (K? R), K + channels of two pores (KTP) and channels K + activated with calcium (Kca). The last group, the K + channels activated by Ca2 +, They consist of three well-defined subtypes: SK channels, IK channels and BK channels. SK, IK and BK refer to single channel conductance (K channel of intermediate, small and large conductance). The SK, IK and BK channels exhibit differences in, for example, voltage and calcium sensitivity, pharmacology, distribution and function. The SK channels are present in many central neurons and ganglia, where their primary function is to hyperpolarize nerve cells after one or several action potentials, to prevent the occurrence of long stretches of epileptogenic activity. SK channels are also present in several peripheral cells, including skeletal muscle, glandular cells, liver cells and T lymphocytes. The transcendence of SK channels in normal skeletal muscle is not clear, but their number is significantly increased in denervated muscle , and the large number of SK channels in the muscle of patients with myotonic muscular dystrophy, which suggests a role in the pathogenesis of the disease. Studies indicate that K + channels can be a therapeutic target in the treatment of a number of diseases, including asthma, cystic fibrosis, chronic obstructive pulmonary disease and rhinorrhea, seizures, vascular spasms, coronary artery spasms, kidney disorders, disease polycystic kidney disease, spasms of bladder, urinary incontinence, obstruction of bladder flow, irritable bowel syndrome, gastrointestinal dysfunction, secretory diarrhea, ischemia, cerebral ischemia, ischemic heart disease, angina, coronary heart disease, traumatic brain injury, psychosis, anxiety, depression, dementia, attention deficit and memory, Alzheimer's disease, dysmenorrhea, narcolepsy, Reynaud's disease, intermittent claudication, Sjorgren's syndrome, migraine, arrhythmia, hypertension, absence attack, myotonic muscular dystrophy, xerostomia, type II diabetes, hyperinsulinemia, work of premature birth, baldness, cancer and immunosuppression.

SUMMARY OF THE INVENTION The present invention resides in the provision of new chemical compounds, capable of selectively modulating SK channels, or subtypes of SK channels. In addition, the invention is directed to pharmaceutical compositions useful for the treatment or alleviation of diseases or disorders associated with the activity of potassium channels, which includes diseases or conditions such as, respiratory diseases, epilepsy, seizures, seizures, absence attacks, vascular spasms. , coronary artery spasms, kidney disorders, polycystic kidney disease, bladder spasms, urinary incontinence, obstruction of bladder flow, erectile dysfunction, gastrointestinal dysfunction, secretory diarrhea, ischemia, cerebral ischemia, ischemic heart disease, angina pectoris, coronary heart disease, ataxia, traumatic brain injury, Parkinson's disease, bipolar disorder, psychosis, schizophrenia, anxiety , depression, mood disorders, dementia, attention deficit and memory, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), dysmenorrhea, narcolepsy, Reynaud's disease, intermittent claudication, Sjorgren's syndrome, arrhythmia, hypertension, myotonic muscular dystrophy, spasticity , xerostomia, type II diabetes, hyperinsulinemia, premature labor, baldness, cancer, irritable bowel syndrome, immune suppression, migraine or pain. Accordingly, in its first aspect, the invention provides novel pyrazolyl quinazoline derivatives of Formula I: an isomer or a mixture of its isomers, an N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2 or 3; X represents O, S or NR '; wherein R 'represents hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl; or, when n is 0 and X is NR ', R' together with Y and together with the nitrogen to which they are attached, form a heterocyclic ring, in which, the heterocyclic ring can be optionally substituted with alkyl or phenyl; Y represents an alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxy-alkyl, alkoxyalkyl, alkenyl, or monocyclic or polycyclic, carbocyclic or heterocyclic group, in which, the carbocyclic or heterocyclic groups, can optionally be substituted one or more times with substituents selected from the group consisting of alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxy-alkyl, alkoxy-alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, halo, haloalkyl, hydroxy , alkoxy, haloalkoxy, cyano, nitro, amino, methylenedioxy, phenyl and morpholinyl; or, when n is 0 and X is NR ', Y together with R' and together with the nitrogen to which they are attached, form a heterocyclic ring, in which, the heterocyclic ring can optionally be substituted with alkyl or phenyl; and R1, R2 and R3 independently from each other, represent hydrogen, alkyl, amino-alkyl, alkyl-amino, alkylamino- alkyl, hydroxy-alkyl, alkoxy-alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, alkoxy-carbonyl, cyano, nitro and amino. In another aspect, the invention provides pharmaceutical compositions comprising an effective amount of a chemical compound of the invention. In additional aspects, the invention relates to the use of a chemical compound of the invention, for the manufacture of a medicament for the treatment or alleviation of diseases or disorders associated with the activity of potassium channels, and to a method of treatment or relief of disorders or conditions receptive to the modulation of potassium channels. Potassium Channel Modulating Agents In its first aspect, the invention provides novel pyrazolyl quinazoline derivatives represented by Formula I an isomer or a mixture of its isomers, an N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2 or 3; X represents 0, S or NR '; wherein R 'represents hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl; or, when n is 0 and X is NR ', R' together with Y and together with the nitrogen to which they are attached form a heterocyclic ring, in which the heterocyclic ring can be optionally substituted with alkyl or phenyl; Y represents an alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxy-alkyl, alkoxyalkyl, alkenyl, or monocyclic or polycyclic, carbocyclic or heterocyclic group, in which, the carbocyclic or heterocyclic groups, can optionally be substituted one or more times with substituents selected from the group consisting of alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxy-alkyl, alkoxy-alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, halo, haloalkyl, hydroxy , alkoxy, haloalkoxy, cyano, nitro, amino, methylenedioxy, phenyl and morpholinyl; or, when n is 0 and X is NR ', Y together with R' and together with the nitrogen to which they are attached, form a heterocyclic ring, in which, the heterocyclic ring can optionally, being substituted with alkyl or phenyl; and R1, R2 and R3 independently of each other, represent hydrogen, alkyl, amino-alkyl, alkyl-amino, alkylamino-alkyl, hydroxy-alkyl, alkoxy-alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, halo, haloalkyl, hydroxy , alkoxy, haloalkoxy, alkoxycarbonyl, cyano, nitro and amino. In a preferred embodiment, the pyrazolyl quinazoline derivative of the invention is a compound of Formula I, wherein n is 0, 1, 2 or 3. In a more preferred embodiment, n is 0, 1 or 2. In a even more preferred embodiment, n is 0 or 1. In a most preferred embodiment, n is 0. In another preferred embodiment, the pyrazolyl quinazoline derivative of the invention is a compound of Formula I, wherein X represents O, S or NR '; wherein R 'represents hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl; or, when n is 0 and X is NR ', R' together with Y and together with the nitrogen to which they are attached form a heterocyclic ring, in which the heterocyclic ring can be optionally substituted with alkyl or phenyl. In a more preferred embodiment, X represents NR '; wherein R 'represents hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl. In an even more preferred embodiment, X represents NR '; wherein R 'represents hydrogen or alkyl.

In a still more preferred embodiment, X represents NR '; wherein R 'represents hydrogen, methyl, ethyl or propyl. In an even more preferred embodiment, X represents NH. In another preferred embodiment, n is 0; X represents NR '; and R 'together with Y and together with the nitrogen to which they are attached form a heterocyclic ring, in which the heterocyclic ring can optionally be substituted with alkyl or phenyl. In a more preferred embodiment, n is 0; X represents NR '; and R 'together with Y and together with the nitrogen to which they are attached form a pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring. In a still preferred embodiment, n is 0; X represents NR '; and R 'together with Y and together with the nitrogen to which they are attached, form a piperidinyl ring. In a third preferred embodiment, the pyrazolyl quinazoline derivative of the invention is a compound of Formula I, wherein Y represents an alkyl, aminoalkyl, alkyl-amino, alkyl-amino-alkyl, hydroxy-alkyl, alkoxy-alkyl group , alkenyl or monocyclic or polycyclic, carbocyclic or heterocyclic, in which the carbocyclic or heterocyclic groups can be optionally substituted one or more times with selected substituents of the group consisting of alkyl, amino-alkyl, alkylamino, alkyl-amino-alkyl, hydroxy-alkyl, alkoxy-alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, nitro, amino , methylenedioxy, phenyl and morpholinyl; or, when n is 0 and X is NR '; And together with R 'and together with the nitrogen to which they are attached, they form a heterocyclic ring, in which, the heterocyclic ring can optionally be substituted with alkyl or phenyl. In a more preferred embodiment, Y represents alkyl, alkenyl or cycloalkyl. In an even more preferred embodiment, Y represents methyl, ethyl, propyl, butyl, pentyl allyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. In a still more preferred embodiment, Y represents ethyl, allyl, cyclopropyl, cyclopentyl, cyclohexyl or cyclooctyl. In an even more preferred embodiment, Y represents cycloalkyl, optionally substituted with alkyl. In a still further preferred embodiment, Y represents cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, optionally substituted with alkyl. In a still further preferred embodiment, Y represents cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, optionally substituted with methyl or tert-butyl. In a still further preferred embodiment, Y represents cyclohexyl substituted with alkyl. In a still further preferred mode, Y represents cyclohexyl substituted with methyl or tert-butyl. In another preferred embodiment, Y represents a monocyclic or carbocyclic polycyclic group, selected from phenyl, naphthyl, or 1, 2, 3, -tetrahydro-naphthyl; or a monocyclic or polycyclic heterocyclic group, selected from pyrrolidinyl, piperidinyl, furanyl, thienyl and pyrronicium which, the phenyl, naphthyl, 1, 2, 3, 4-tetrahydro-naphthyl, pyrrolidinyl, piperidinyl, furanyl, thienyl and pyrrolyl groups, they may be optionally substituted once or twice with substituents selected from the group consisting of alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxy-alkyl, alkoxy-alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, nitro and amino. In a more preferred embodiment, Y represents phenyl, naphthyl, 1, 2, 3, 4-tetrahydro-naphthyl, pyrrolidinyl, piperidinyl, furanyl, thienyl or pyrrolyl; wherein the phenyl, naphthyl, 1,2,3-tetrahydro-naphthyl, pyrrolidinyl, piperidinyl, furanyl, thienyl and pyrrolyl groups can be optionally substituted once or twice with substituents selected from the group consisting of alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxy-alkyl, alkoxy-alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, nitro , and not me. In an even more preferred embodiment, Y represents phenyl, naphth-1-yl, naphth-2-yl, 1,2,3-tetrahydro-naphth-1-yl, 1, 2, 3, 4-tetrahydro-naphth- 2-yl, pyrrolidin-1-yl, piperidin-1-yl, piperidin-4-yl, furan-2-yl, furan-3-yl, thien-1-yl, thien-2-yl, pyrrole-1- ilo or pyrrole-2-yl; wherein the phenyl, naphthyl, 1, 2, 3, 4-tetrahydro-naphthyl-pyrrolidinyl, piperidinyl, furanyl, thienyl and pyrrolyl groups can be optionally substituted once or twice with substituents selected from the group consisting of alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxy-alkyl, alkoxy-alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, nitro and amino. In a still more preferred embodiment, the phenyl, naphthyl, 1, 2, 3, -tetrahydro-naphthyl, pyrrolidinyl, piperidinyl, furanyl, thienyl, and pyrrolyl groups can optionally be substituted once or twice with substituents selected from the group consisting of of alkyl, halo, haloalkyl, alkoxy. In an even more preferred modality, the groups phenyl, naphthyl, 1, 2, 3, 4-tetrahydro-naphthyl, pyrrolidinyl, piperidinyl, furanyl, thienyl and pyrrolyl, can optionally be substituted once or twice with substituents selected from the group consisting of methyl, ethyl, propyl, chloro , fluoro, bromo, trifluoromethyl, methoxy or ethoxy. In a further preferred embodiment, Y represents a monocyclic or polycyclic carbocyclic group, selected from phenyl, naphthyl, 1,2,3-tetrahydro-naphthyl and indanyl groups, in which the carbocyclic groups may optionally be substituted one or more times with substituents selected from the group consisting of alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxy-alkyl, alkoxy-alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy , cyano, nitro, amino, methylenedioxy, phenyl and morpholinyl. In a still further preferred embodiment, Y represents phenyl, naphthyl, 1,2,3,4-tetrahydro-naphthyl and indanyl, in which the carbocyclic groups can optionally be substituted once or twice with substituents selected from the group consisting of of alkyl, halo, haloalkyl, alkoxy, methylenedioxy, phenyl and morpholinyl. In a still further preferred mode, Y represents phenyl, naphthyl, 1, 2, 3, 4-tetrahydro-naphthyl and indanyl, in which the carbocyclic groups can be optionally substituted once or twice with substituents selected from the group consisting of methyl, tert-butyl, fluoro , chlorine, bromine, iodine, trifluoromethyl, methoxy, methylenedioxy, phenyl and morpholinyl. In a still further preferred mode, Y represents phenyl, optionally substituted once or twice with substituents selected from the group consisting of methyl, tert-butyl, fluoro, chloro, bromo, iodo, trifluoromethyl, methoxy, methylenedioxy, phenyl and morpholinyl. In a still further preferred mode, Y represents phenyl, optionally substituted with alkyl, halo, haloalkyl, alkoxy, methylenedioxy, phenyl or morpholinyl. In a still further preferred mode, Y represents phenyl, optionally substituted with methyl, tert-butyl, fluoro, chloro, bromo, iodo, trifluoromethyl, methoxy, methylenedioxy, phenyl or morpholinyl. In a still further preferred mode, Y represents a heterocyclic group, in which the carbocyclic or heterocyclic groups can be optionally substituted one or more times with substituents selected from the group consisting of alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxy alkyl, alkoxy-alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, nitro, amino. In a still further preferred embodiment, the Y mode represents tetrahydropyranyl, pyrrolidinyl, piperidinyl, furanyl, thienyl, pyrrolyl, pyridinyl, indolyl or quinolinyl. In a more preferred embodiment, Y represents tetrahydropyranyl, pyridinyl, indolyl or quinolinyl. In a fourth preferred embodiment, the pyrazolyl quinazoline derivative of the invention is a compound of Formula I, wherein R 1, R 2 and R 3 independently of each other, represent hydrogen, alkyl, amino-alkyl, alkyl-amino, alkyl-amino -alkyl, hydroxy-alkyl, alkoxy-alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, alkoxy-carbonyl, cyano, nitro and amino. In a fifth preferred embodiment, the pyrazolyl quinazoline derivative of the invention is a compound of Formula I, wherein R 1, R 2 and R 3 independently of each other, represent hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, halo, haloalkyl, hydroxy , alkoxy, haloalkoxy, alkoxycarbonyl, cyano, nitro or amino. In a more preferred embodiment, R1, R2 and R3 independently of each other, represent alkyl, cycloalkyl or cycloalkyl-alkyl. In an even more preferred embodiment, R1, R2 and R3 independently of each other, represent hydrogen or alkyl. In a still more preferred embodiment, R1, R2 and R3, independently of each other, represent methyl, ethyl or propyl. In an even more preferred embodiment, R1 and R2 independently from each other, represent hydrogen or alkyl; and R3 represents hydrogen. In a further preferred embodiment, R1 and R2 independently from each other, represent alkyl; and R3 represents hydrogen. In a still further preferred embodiment, R1 and R2 represent methyl or isopropyl; and R3 represents hydrogen. In a still further preferred embodiment, R1 and R2 represent methyl; and R3 represents hydrogen. In a still further preferred embodiment, R1 and R2 represent isopropyl; and R3 represents hydrogen. In a still further preferred mode, R1 represents methyl; and R2 and R3 represents hydrogen. In a still further preferred embodiment, R1, R2 and R3 represents hydrogen. In a sixth preferred embodiment, the pyrazolyl quinazoline derivative of the invention is a compound of Formula I, wherein n is 0; X represents O, S or NR '; wherein R 'represents hydrogen, methyl, ethyl or propyl; Y represents alkyl, alkenyl, cycloalkyl, alkylcycloalkyl; R1 and R2 represent methyl or isopropyl; and R3 represents hydrogen. In a more preferred embodiment, n is 0; X represents NH; Y represents alkyl, alkenyl, cycloalkyl, alkyl-cycloalkyl, naphthyl, 1, 2, 3, 4-tetrahydro-naphthyl indanyl, tetrahydropyranyl, pyridinyl, indolyl or quinolinyl; R1 and R2 represent methyl or isopropyl; and R3 represents hydrogen. In a seventh preferred embodiment, the pyrazolyl quinazoline derivative of the invention is a compound of Formula I, wherein n is 0; X represents NR '; wherein R 'represents hydrogen, methyl, ethyl or propyl; Y represents alkyl (ethyl, propyl, butyl), cycloalkyl (cyclopropyl, cyclopentyl, cyclohexyl, cyclooctyl), cycloalkyl-alkyl or alkenyl (allyl), piperidinyl or phenyl, in which, the phenyl can be optionally substituted once or twice with halo or trifluoromethyl; and R1, R2 and R3 independently from each other, represent methyl, ethyl or propyl. In an eighth preferred embodiment, the pyrazolyl quinazoline derivative of the invention is a compound of Formula I, wherein n is 0 or 1; X represents NH; Y represents phenyl, optionally substituted once or twice with substituents selected from the group consisting of alkyl, halo, haloalkyl, alkoxy, methylenedioxy, phenyl and morpholinyl; R1 and R2 represent methyl or isopropyl; and R3 represents hydrogen. In a more preferred embodiment, n is 0; X represents NH; Y represents phenyl, optionally substituted once or twice with substituents selected from the group consisting of alkyl, halo, haloalkyl, alkoxy, methylenedioxy, phenyl and morpholinyl; R1 and R2 represent methyl or isopropyl; and R3 represents hydrogen. In an even more preferred embodiment n is 1; X represents NH; Y represents phenyl, optionally substituted once or twice with substituents selected from the group consisting of alkyl, halo, haloalkyl, alkoxy, methylenedioxy, phenyl and morphillinyl; R1 and R2 represents methyl or isopropyl; and R3 represents hydrogen. In an even more preferred embodiment n is 1; X represents NH; Y represents phenyl, optionally substituted once or twice with substituents selected from the group consisting of halo or haloalkyl; R1 and R2 represents methyl; and R3 represents hydrogen. In a ninth preferred embodiment, the pyrazolyl quinazoline derivative of the invention is a compound of Formula I, wherein n is 0; X represents NR '; R 'together with Y and together with the nitrogen to which they are attached, form a pyrrolidinyl or piperidinyl ring; and R1, R2 and R3, independently of each other, represent methyl, ethyl or propyl. In a tenth preferred embodiment, the pyrazolyl quinazoline derivative of the invention is a compound of Formula I, wherein n is 0; X represents NR '; and R 'together with Y and together with the nitrogen to which they are attached, form a pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring; R1 and R2 independently from each other represent methyl, ethyl or propyl; and R3 represents hydrogen. In a preferred eleventh embodiment, the pyrazolyl quinazoline derivative of the invention is a compound of Formula I, wherein n is 1; and X represents NR '; wherein R 'represents hydrogen, methyl, ethyl or propyl; Y represents furanyl, thienyl or phenyl, in which phenyl can be optionally substituted once or twice with halo or trifluoromethyl; and R1, R2 and R3, independently of each other, represent methyl, ethyl or propyl. In a more preferred embodiment, the pyrazolyl quinazoline derivative of the invention is: [2- (3,5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -propylamine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -ethylamine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] - diethyl amine; Butyl- [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; Allyl- [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; Cyclopropyl- [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; Cyclopentyl- [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; Cyclohexyl- [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; Cycloheptyl- [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; Cyclooctyl- [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; 2- (3, 5-Dimethyl-pyrazol-1-yl) -4-piperidin-1-yl-quinazoline; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -piperidin-4-yl-amine; Benzyl- [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; (4-Chloro-benzyl) - [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; (3,4-Difluoro-benzyl) - [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -furan-2-ylmethyl-amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -thiophen-2-ylmethyl-amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -phenyl-amine; (4-Chloro-phenyl) - [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; (3-Chloro-phenyl) - [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; (2-Chloro-phenyl) - [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; (3,4-Dichloro-phenyl) - [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; (4-Bromo-phenyl) - [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] - (4-trifluoromethyl-phenyl) -amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] - (3-trifluoromethyl-phenyl) -amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] - (3-methoxy-phenyl) -amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -p-tolyl-amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -qui azolin-4-yl] -m- tolyl-amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -o-tolyl-amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -naphthalen-2-yl-amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] - (1,2,3,4-tetrahydro-naphthalen-1-yl) -amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] - (2-pyrrolidin-1-yl-ethyl) -amine; Cyclohexyl- [2- (3-methyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; S- [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] - (S) -1,2,3,4-tetrahydro-naphthalene-1-yl-amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] - (1-ethyl-propyl) -amine; [2- (3,5-Diisopropyl-pyrazol-1-yl) -quinazolin-4-yl] - (4-methyl-cyclohexyl) -amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -pyridin-2-yl-amine; [2- (3, 5-Dimethyl-1-pyrazol-1-yl) -quinazolin-4-yl] - (4-methyl-cyclohexyl) -amine; (4-tert-Butyl-cyclohexyl) - [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] - (tetrahydro-pyran-4-yl) -amine; Cicyclohexyl- [2- (3, 5-diisopropyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -indan-2-yl-amine; Benzo [1,3] dioxol-5-yl- [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; (3,5-Bis-trifluoromethyl-phenyl) - [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] - (4-morpholin-4-yl-phenyl) -amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -quinolin-8-yl-amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] - (4-iodo-phenyl) -amine; Biphenyl-4-yl- [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; [2- (3, 5-Dimethyl-pyrazol-l-yl) -quinazolin-4-yl] - (1-H-indol-7-yl) -amine; or Cicyclohexyl- (2-pyrazol-l-yl-quinazolin-4-yl) -amine; or a pharmaceutically acceptable salt thereof. Any combination of two or more of the embodiments described herein is considered within the scope of the present invention.

Definition of Substituents In the context of this invention, halo represents fluoro, chloro, bromo or iodo. Thus, a trihalomethyl group represents, for example, a trifluoromethyl group, a trichloromethyl group and similar trihalo-substituted methyl groups. In the context of this invention, a haloalkyl group designates an alkyl group as defined herein, in which, the alkyl group is substituted one or more times with halo. Preferred haloalkyl groups of the invention include trihalomethyl, preferably, trifluoromethyl. In the context of this invention, an alkyl group designates a univalent saturated, straight or branched hydrocarbon chain. The hydrocarbon chain preferably contains from one to eighteen carbon atoms (Ci-iß alkyl) and preferably from one to six carbon atoms (C?-6 alkyl, lower alkyl), which includes pentyl, isopentyl, neopentyl, pentyl tertiary, hexyl and isohexyl. In a preferred embodiment, alkyl represents a CJ-C4 alkyl group, which includes butyl, isobutyl, secondary butyl and tertiary butyl. In a preferred embodiment of this invention, alkyl represents a C? ~3 alkyl group, which may in particular be methyl ethyl, propyl or isopropyl.

In the context of this invention, an alkenyl group designates a carbon chain containing one or more double bonds, including di-ions, tri-ennes and polyenes. In a preferred embodiment, the alkenyl group of the invention comprises, from two to eight carbon atoms (C2-8 alkenyl), more preferred two to six carbon atoms (C2-6 alkenyl), which includes at least one bond double. In a more preferred embodiment, the alkenyl group of the invention is ethenyl; 1 or 2-propenyl; 1, 2, or 3-butenyl or 1,3-butenyl; 1, 2, 3, 4, or 5-hexenyl or 1,3-hexenyl or 1, 3, 5-hexenyl; 1, 2, 3, 4, 5, 6, or 7-octenyl, or 1,3-octenyl, or 1, 3, 5-octenyl or 1, 3, 5, 7-octenyl. In the context of this invention, a cycloalkyl group designates a cyclic alkyl group, preferably, which contains from three to ten carbon atoms (C3-cycloalkyl), preferably from three to eight carbon atoms (C3-cycloalkyl), which includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. In the context of this invention, a cycloalkyl-alkyl group designates a cycloalkyl group as defined above, in which, a cycloalkyl group is substituted in an alkyl group, as defined above. Examples of preferred cycloalkyl-alkyl groups of the invention include cyclopropylmethyl and cyclopropylethyl. In the context of this invention, an alkoxy group designates an "alkyl-O-" group, wherein alkyl is as defined above. In the context of this invention, a haloalkoxy group designates an alkoxy group as defined herein, in which, the alkoxy group is substituted one or more times with halo. Preferred haloalkoxy groups of the invention include, trihalomethoxy, preferably, trifluoromethoxy. In the context of this invention, an amino group can be a primary (-NH2), secondary (-NH-alkyl), or tertiary (-N (alkyl) 2) amino group, that is, it can be substituted once or twice with an alkyl group as defined above. In the context of this invention, a monocyclic or polycyclic carboxylic group designates a mono- or polycyclic hydrocarbon group in which the group can be in particular an aromatic hydrocarbon group, i.e., a mono or polycyclic aryl group, or a saturated hydrocarbon group, or a partially saturated hydrocarbon group. The preferred poly-carbocyclic group is the bicyclic carbocyclic groups. In the context of this invention, a monocyclic or polycyclic carbocyclic group designates a monocyclic or polycyclic hydrocarbon group. Group examples Preferred carbocyclic moieties of the invention include cycloalkyl, phenyl, naphthyl, indenyl, azulenyl, anthracenyl and fluorenyl. The most preferred carbocyclic groups of the invention include phenyl, naphthyl and 1, 2, 3, 4-tetrahydro-naphthyl. In the context of this invention a monocyclic or polycyclic heterocyclic group designates a mono or polycyclic group, in which the group maintains one or more heteroatoms in its ring structure. Preferred heteroatoms include nitrogen (N), oxygen (0), and sulfur (S). One or more of the ring structures may in particular be aromatic (i.e., a heteroaryl), saturated or partially saturated. Preferred heterocyclic monocyclic groups of the invention include 5- and 6-membered heterocyclic monocyclic groups. Preferred poly-heterocyclic groups of the invention are the bicyclic heterocyclic groups. Examples of preferred heterocyclic monocyclic groups of the invention include pyrrolidinyl, in particular, pyrrolidin-1-yl, pyrrolidin-2-yl and pyrrolidin-3-yl; piperidinyl, in particular, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl and piperidin-4-yl; furanyl, in particular furan-2-yl and furan-3-yl; thienyl, in particular, thien-2-yl and thien-3-yl; and pyrrolyl, in particular, pyrrol-1-yl, pyrrol-2-yl and pyrrole-3-yl.

Isomers It will be appreciated by those skilled in the art, that the compounds of the present invention can exist in forms, including enantiomers, diastereomers, as well as geometric isomers (cis-trans isomers). The invention includes all isomers and any mixtures thereof which include racemic mixtures. The racemic forms can be resolved in the optical antipodes by known methods and techniques. One way of separating the enantiomeric compounds (including enantiomeric intermediates), is by the use of an optically active amine and releasing the resolved diastereomeric salt, by treatment with an acid. Another method to solve racemates in the optical antipodes is based on chromatography in an optical active matrix. The racemic compounds of the present invention can thus be resolved in their optical antipodes, for example, by fractional crystallization of D or L salts (tartrates, mandelates or camphorsulfonate) for example. The chemical compounds of the present invention can also be resolved by the formation of diastereomeric amides by reaction of the chemical compounds of the present invention with an optically active activated carboxylic acid, such as that derivative of (+) or (-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) acid canfaánico or by the formation of diastereomeric carbamates by reaction of the chemical compound of the present invention with an optically active chloroformate or the like. Additional methods for resolution of optical isomers are known in the art. Such methods include those described by Jaques J. Collet A, & Wilen S in "Enantiomers, Racemates, and Resolutions", Joh Wiley and Sons, New York (1981). ' Active optical compounds can also be prepared from optical active starting materials or intermediates.

Pharmaceutically Acceptable Salts The chemical compound of the invention can be provided in any suitable form for the proposed administration. Suitable forms include pharmaceutically (i.e., physiologically) acceptable salts and pharmaceutically acceptable forms or pre-forms of the chemical compound of the invention. Examples of pharmaceutically acceptable addition salts include, without limitation, non-toxic organic and inorganic acid addition salts, such as hydrochloride derived from hydrochloric acid, hydrobromide derived from hydrobromic acid, nitrate derived from nitric acid, perchlorate derived from perchloric acid, phosphate phosphoric acid derivative, sulphate derived from sulfuric acid, formate derived from formic acid, acetate derived from acetic acid, acononate derived from aconitic acid, ascorbate derived from ascorbic acid, benzenesulfonate derived from benzenesulfonic acid, benzoate derived from benzoic acid, cinnamate derived from cinnamic acid, citrate derived from citric acid, embonate derived from embonic acid, enanthate derived from enanthic acid, fumarate derived from fumaric acid, glutamate derived from glutamic acid, glycollate derived from glycolic acid, lactate derived from lactic acid, maleate derived from maleic acid , malonate derived from malonic acid, mandelate derived from mandelic acid, methanesulfonate derived from methanesulfonic acid, naphthalene-2-sulfonate derived from naphthalene-2-sulfonic acid, phthalate derived from phthalic acid, derivative salicylate from salicylic acid, sorbate derived from sorbic acid , stearate derived from ac stearic acid, succinic acid derivative derived from succinic acid, tartrate derived from tartaric acid, toluene-p-sulfonate derived from p-toluene sulphonic acid and the like. Such salts can be formed by methods well known and described in the art. Other acids such as oxalic acid, which may not be considered pharmaceutically acceptable, may be useful in the preparation of salts employed as intermediates in obtaining a chemical compound of the invention and its pharmaceutically acceptable acid addition salt. Metallic salts of a chemical compound of the invention include alkyl metal salts such as the sodium salt of a chemical compound of the invention which contains a carboxy group. In the context of this invention the "onium salts" of N-containing compounds are also contemplated as pharmaceutically acceptable salts. Preferred "onium salts" include the alkyl-onium salts, the cycloalkyl-onium salts and the cycloalkylalkyl-onium salts. The chemical compound of the invention can be provided in dissolvable or indissoluble forms, together with a pharmaceutically acceptable solvent, such as water, ethanol and the like. Dissolvable forms can also include hydrated forms such as monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate, and the like. In general, the dissolvable forms are considered equivalent to the indissoluble forms for the purposes of this invention.

Methods of Preparation The chemical compounds of the invention can be prepared by conventional methods of chemical synthesis, for example, those described in the working examples. The starting materials for the processes described in the present application are known or can be readily prepared by conventional methods from commercially available chemicals. The final products of the reactions described herein can be isolated by conventional techniques, for example, by extraction, crystallization, distillation, chromatography, etc.

Biological Activity The chemical compounds of the invention have been subjected to in vitro experiments and are particularly employed as potassium channel modulating agents. More particularly, the compounds of the invention are capable of selectively modulating SKI, SK2 and / or SK3 channels. Therefore, in another aspect, the invention relates to the use of a chemical compound of the invention for the manufacture of medicaments, wherein the medicament can be used for the treatment or alleviation of a disease or a disorder associated with the activity of potassium channels, in particular, SK channels, more particularly, SKI, SK2 and / or SK3 channels.

In a preferred embodiment, the disease or a disorder associated with the activity of potassium channels, is a respiratory disease, epilepsy, seizures, seizures, absence attacks, vascular spasms, coronary artery spasms, kidney disorders, polycystic kidney disease, spasms of bladder, urinary incontinence, obstruction of bladder flow, erectile dysfunction, gastrointestinal dysfunction, secretory diarrhea, ischemia, cerebral ischemia, ischemic heart disease, angina pectoris, coronary heart disease, ataxia, traumatic brain injury, Parkinson's disease, bipolar disorder , psychosis, schizophrenia, anxiety, depression, mood disorders, dementia, attention deficit and memory, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), dysmenorrhea, narcolepsy, Reynaud's disease, intermittent claudication, Sjorgren's syndrome, arrhythmia, hypertension , myotonic muscular dystrophy, spasticity, xerostomia, d Type II diabetes, hyperinsulinemia, preterm labor, baldness, cancer, irritable bowel syndrome, immune suppression, migraine or pain. In a more preferred embodiment, the disease or a disorder associated with the activity of potassium channels is a respiratory disease, urinary incontinence, erectile dysfunction, anxiety, epilepsy, psychosis, schizophrenia, amyotrophic lateral sclerosis (ALS). or pain In another preferred embodiment, the disease or a disorder associated with the activity of potassium channels is a respiratory disease, in particular asthma, cystic fibrosis, chronic obstructive pulmonary disease (COPD) or rhinorrhea. In a third preferred embodiment, the disease or a disorder associated with the activity of potassium channels is urinary incontinence. In a fourth preferred embodiment, the disease or a disorder associated with the activity of potassium channels is epilepsy, seizure, seizure attack, or seizure. In a fifth preferred embodiment, the disease or a disorder associated with the activity of potassium channels is a respiratory disease, in particular asthma, cystic fibrosis, chronic obstructive pulmonary disease (COPD) or rhinorrhea. The tested compounds all show a biological activity in the micromolar and sub-micromolar range, i.e., from about 1 up to 100 μM. Preferred compounds of the invention, show a biological activity determined as described herein in the sub-micromolar and micromolar range, ie from about 0.1 to about 10 μM.

Pharmaceutical Compositions In yet another aspect, the invention provides novel pharmaceutical compositions comprising a therapeutically effective amount of the chemical compound of the invention. While a chemical compound of the invention for use in therapy can be administered in the form of a crude chemical compound, it is preferred to introduce the active ingredient, optionally in the form of a physiologically acceptable salt, into a pharmaceutical composition together with one or more adjuvants, excipients, carriers and / or diluents. In one embodiment, the invention provides pharmaceutical compositions, comprising the chemical compound of the invention, or a pharmaceutically acceptable salt or derivative thereof, together with one or more pharmaceutically acceptable carriers, therefore and, optionally, other therapeutic ingredients and / or prophylactics. The carriers can be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof. The pharmaceutical compositions of the invention may be those suitable for oral, rectal, bronchial, nasal, topical (including buccal and sub-lingual), transdermal, vaginal or parenteral administration (including injection or cutaneous infusion, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral, intraocular) or that in a form suitable for administration by inhalation or insultation, which includes administration of powders and liquid aerosol, or by sustained release systems. Examples suitable for sustained release systems include semipermeable matrices of solid hydrophobic polymers, containing the compound of the invention, said matrices can be in the form of shaped articles, for example films or microcapsules. The chemical compound of the invention, together with a conventional adjuvant, carrier or diluent, can thus be placed in the form of pharmaceutical compositions and dosage units thereof. Such forms include solids, and in particular tablets, filled capsules, powders and pellet forms, and liquids, particulate aqueous and non-aqueous solutions, suspensions, emulsions, elixirs and capsules filled therewith, all for oral use, suppositories for administration rectal, and sterile injectable solutions for parenteral use. Such pharmaceutical compositions and unit dosage forms, therefore, may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such forms unit dosage may contain any suitable effective amount of the active ingredient according to the daily dosage range intended to be employed. The chemical compound of the present invention can be administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a chemical compound of the invention or a pharmaceutically acceptable salt of a compound of the invention. To prepare pharmaceutical compositions from a chemical compound of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Preparations in solid form include powders, tablets, pills, capsules, troches, suppositories and dispersible granules. A solid carrier may be one or more substances, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents or an encapsulated material. In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier, which has the necessary binding capacity in Proper proportions and compacted in the desired shape and size. The powders and tablets preferably contain from five to ten to about seventy percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier that provides a capsule, in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with this . Similarly, the troches and dragees are included. Tablets, powders, capsules, pills, troches and lozenges can be used as solid forms suitable for oral administration. For the preparation of suppositories, a low melting wax, such as a mixture of fatty acid glyceride or cocoa butter, is first melted and the active component is dispersed homogeneously therein, by stirring it. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify. The compositions suitable for vaginal administration, can be presented as presarios, tampons, creams, gels, cakes, foams or sprays containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate. Liquid preparations include, solutions, suspensions and emulsions, for example, water or water-propylene glycol solutions. For example, liquid parenteral injection preparations can be formulated as solutions in aqueous polyethylene glycol solution. The chemical compound according to the present invention can thus be formulated for parenteral administration (for example, by injection, for example, bolus injection or continuous infusion), and can be presented as a unit dose in ampoules, prefilled syringes, small volume infusion or in multiple dose containers, with an added condom. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solids or by lyophilization of solution, by constitution with a suitable vehicle, eg, sterile, pyrogen-free water, before use. Adequate aqueous solutions can be prepared for oral use, dissolving the active component in water and adding suitable colorants, flavors, stabilizers and thickeners, as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water, with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose or other well-known suspending agents. Also included are preparations in solid forms, which are intended to be converted, soon before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. For topical administration to the epidermis, the chemical compound according to the invention can be formulated in ointments, creams or lotions, or as a transdermal patch. The ointments and creams can, for example, be formulated with an aqueous or oily base, with the addition of suitable thickening and / or gelling agents. Lotions can also be formulated with an aqueous or oily base and in general, they will also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents or coloring agents. Compositions suitable for topical administration in the mouth include, lozenges comprising the active agent in a flavored base, usually sucrose and acacia or tragacanth; pills comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouth rinses comprising the active ingredient in a suitable liquid carrier. The solutions or suspensions are applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette or atomizer. The compositions can be provided in single or multiple dose form. In the latter case of a dropper or pipette, this can be achieved by the patient, administering a predetermined, appropriate volume of the suspension or solution. In the case of an atomizer, this can be achieved, for example, by means of a metering atomizing spray pump. Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurized package with a suitable propellant, such as a chlorofluorocarbon (CFC) for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of the drug can be controlled by provision of a metering valve. Alternatively, the active ingredients may be provided in the form of a dry powder, for example, a powder mixture of the compound in a suitable powder base, such as lactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidone (PVP). Conveniently, the powder carrier will form a gel in the nasal cavity. The powder composition can be presented in unit dosage form for example, in capsules or cartridges of, for example, gelatin or packets in ampoules, from which the powder can be administered by means of an inhaler. In compositions proposed for administration to the respiratory tract, including intranasal compositions, the compound in general will have a small particle size for example, of the order of 5 microns or less. Such particle size can be obtained by means known in the art, for example, by micronization. When desired, compositions adapted to give sustained release of the ingredient may be employed. active. The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as tablets, capsules and powders packed in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, pill or lozenge itself, or it can be the appropriate number of any of these in packaged form. Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions. Additional details or formulation and administration techniques can be found in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton, PA). A therapeutically effective dose refers to such an amount of the active ingredient which alleviates the symptoms or conditions. The therapeutic efficacy and toxicity, for example, ED50 and LD50, can be determined by standard pharmacological procedures in cell cultures or experimental animals. The dose ratio between the toxic and therapeutic effects, they are the therapeutic index and can be expressed by the LD50 / ED50 ratio. Preferred are pharmaceutical compositions which exhibit high therapeutic indices. The administered dose must, of course, be carefully adjusted with the age, weight and condition of the individual to be treated, as well as the route of administration, dosage form and regime, and the desired result, and the exact dosage must your position, be determined by the specialist. The current dosage depends on the nature and severity of the disease to be treated and the route of administration, and is within the discretion of the specialist, and can be varied by titration of the dosage with the particular circumstances of this invention, to produce the desired therapeutic effect. However, it is now contemplated that pharmaceutical compositions containing from about 0.1 to about 500 mg of the active ingredient per individual dose, preferably from about 1 to about 100 mg, more preferably from about 1 to about 10 mg, are suitable for treatments therapeutic The active ingredient can be administered in one or several doses per day. A satisfactory result can, under certain circumstances, be obtained at such a low dosage as 0.1 μg / kg i.v. and 1 μg / kg p.o. The upper limit of the dosage range is currently considered to be approximately 10 mg / kg i.v. and 100 mg / kg p.o. Preferred ranges are from about 0.1 μg / kg to about 10 mg / kg / day i.v., and from about 1 μg / kg to about 100 mg / kg / day p.o.

Methods of Therapy In another aspect, the invention provides a method for the preparation, treatment or alleviation of a disease or disorder or a condition of a living animal body, including a human, in which, the disease, disorder or condition, is responsive to the modulation of potassium channels, in particular, SK channels, and in which, the method comprises, administering to such a living animal body including a human in need thereof, a therapeutically effective amount of a compound of the invention. The preferred indications contemplated according to the invention are those stated above. At present, it is contemplated that the proper dosage ranges are 0.1 to 1000 milligrams per day, 10-500 milligrams daily, and especially, 30-100 milligrams daily, depending on how usual it is after of the exact mode of administration, the form in which it is administered, the indication to which the administration is directed, the subject involved and the body weight of the subject involved, and also, the preference and experience of the specialist or veterinarian in charge. A satisfactory result can be obtained in certain cases, at a dosage as low as 0.005 mg / kg i.v., and 0.01 mg / kg p.o. The upper limit of the dosage range is approximately 10 mg / kg i.v. and 100 mg / kg p.o. Preferred ranges are from about 0.001 to about 1 mg / kg i.v. and from about 0.1 to about 10 mg / kg p.o.

DETAILED DESCRIPTION OF THE INVENTION EXAMPLES The invention is further illustrated with reference to the following examples, which are not intended to be in any way limiting the scope of the invention as claimed. Example 1 Preparatory Example Method A [2- (3,5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -propylamine Hydrochloride (Compound Al) 2,4-Dichloroquinazoline (600 mg, 3.01) was dissolved mmol) in acetonitrile (10 ml). Propylamine (200 mg, 3.3 mmol) and triethylamine (2.1 ml, 15 mmol) were added. The mixture was stirred at room temperature overnight. Filtration and evaporation of the filtrate gave a yellow solid, which was dissolved in ethyl acetate and washed three times with water. Drying (magnesium sulfate), filtration and evaporation gave (2-chloro-quinazolin-4-yl) -propylamine as a yellow solid. (2-Chloro-quinazolin-4-yl) -propylamine (450 mg, 2.03 mmol) was dissolved in acetonitrile (7.5 ml) and 3,5-dimethylpyrazole (215 mg, 2.23 mmol) was added. The mixture was heated in a microwave oven at 170 ° C for 20 minutes. Filtration afforded [2- (3,5-dimethylpyrazol-1-yl) -quinazolin-4-yl] -propylamine hydrochloride (290 mg, 51%) as a pale yellow crystalline compound. Mp. 208 ° C. The following compounds were prepared in analogy with these. [2- (3,5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -ethylamine hydrochloride (Compound A2) Prepared according to Method A, from 2,4-dichloroquinazoline, ethylamine and 3, 5-dimethylpyrazole. P.f. 286 ° C. [2- (3, 5-Dimethyl-pyrazol-1-yl) -qulnazolin-4-yl] -diethyl-amine hydrochloride (Compound A3) Was prepared according to Method A, starting from of 2,4-dichloroquinazoline, diethylamine and 3,5-dimethylpyrazole.

P.f. 156.3 ° C. Butyl- [2- (3,5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine hydrochloride (Compound A4) Prepared according to Method A, from 2,4-dichloroquinazoline , butylamine and 3,5-dimethylpyrazole.

P.f. 98.4 ° C. Allyl- [2- (3,5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine hydrochloride (Compound A5) Prepared according to Method A, from 2,4-dichloroquinazoline , allylamine and 3,5-dimethylpyrazole.

P.f. 211-212 ° C. Cyclopropyl- [2- (3,5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine hydrochloride (Compound A6) Prepared according to Method A, starting from 2-dichloroquinazoline, cyclopropylamine and 3,5-dimethylpyrazole. P.f. 254 ° C. Cyclopentyl- [2- (3,5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine hydrochloride (Compound A7) Prepared according to Method A, starting from 2-dichloroquinazoline, Cyclopentylamine and 3,5-dimethylpyrazole Pf 263.2 ° C. Cyclohexyl- [2- (3,5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine hydrochloride (Compound A8) Prepared according to Method A, starting from of 2,4-dichloroquinazoline, cyclohexylamine and 3,5-dimethylpyrazole P.f. 137.6-142.7 ° C. Cycloheptyl- [2- (3,5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine hydrochloride (Compound A9) Prepared according to Method A, from 2,4-dichloroquinazoline , cycloheptylamine and 3,5-dimethylpyrazole. P.f. 207 ° C. Ciclooctyl- [2- (3,5-dimethyl-pyrazol-l-yl) -quinazolin-4-yl] -amine hydrochloride (AlO Compound) Prepared according to Method A, from 2,4-dichloroquinazoline , cyclooctylamine and 3,5-dimethylpyrazole. P.f. 211 ° C. 2- (3,5-Dimethyl-pyrazol-1-yl) -4-piperidin-1-yl-quinazoline hydrochloride (Compound All) Prepared according to Method A, from 2,4-dichloroquinazoline, piperidine and 3,5-dimethylpyrazole.

P.f. 157 ° C. Benzyl- [2- (3,5-dimethyl-1-pyrazol-1-yl) -quinazolin-4-yl] -amine hydrochloride (Compound A12) Prepared according to Method A, from 2,4-dichloroquinazoline , benzylamine and 3,5-dimethylpyrazole.

P.f. 160.2 ° C. (4-Chloro-benzyl) - [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine hydrochloride (Compound A13) Prepared according to Method A, starting from of 2,4-dichloroquinazoline, 4-chlorbenzylamine and 3,5-dimethylpyrazole. CL-ERI-EMAR [M + H] + 364.1319 Da. Cale. 364. 132898 Da (3,4-Difluoro-benzyl) - [2- (3,5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine hydrochloride (Compound A14) Prepared according to Method A, from 2,4-dichloroquinazoline, 3,4-difluorobenzylamine and 3,5-dimethylpyrazole. P.f. 165 ° C. [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] - (1, 2, 3, 4-tetrahydro-naphthalen-1-yl) -amine hydrochloride (Compound A15) prepared in accordance with Method A, starting with 2,4-dichloroquinazoline, 1, 2, 3, 4-tetrahydro-1-naphthylamine and 3,5-dimethylpyrazole. P.f. 221 ° C. S- [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] - (S) -1,2,3,4-tetrahydro-naphthalen-1-yl-amine hydrochloride ( Compound A16) Prepared according to Method A, from 2,4-dichloroquinazoline, S-1, 2, 3, -tetrahydro-1-naphthylamine and 3, 5-dimethylpyrazole. P.f. 214 ° C. Cisolhexyl- [2- (3-methyl-pyrazol-1-yl) -quinazolin-4-yl] -amine hydrochloride (Compound A17) Prepared according to Method A, from 2,4-dichloroquinazoline, cyclohexylamine and 3-methylpyrazole.

P.f. 269-274.3 ° C. [2- (3,5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] - (1-ethyl-propyl) -amine hydrochloride (Compound A18) Was prepared according to Method A, starting from of 2,4-dichloroquinazoline, 3-aminopentane and 3,5-dimethylpyrazole. P.f. 96.4 ° C. [2- (3,5-Diisopropyl-pyrazol-l-yl) -quinazolin-4-yl] - (4-methyl-cyclohexyl) -amine hydrochloride (Compound A19) Prepared according to Method A, starting from of 2,4-dichloroquinazoline, 4-methylcyclohexylamine and 3,5-diisopropylpyrazole. P.f. 134.6 ° C. [2- (3,5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] - (4-methyl-cyclohexyl) -amine hydrochloride (Compound A20) Prepared according to Method A, starting from of 2,4-dichloroquinazoline, 4-methylcyclohexylamine and 3,5-dimethylpyrazole. P.f. 80.4-81.6 ° C. (4-tert-Butyl-cyclohexyl) - [2- (3,5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine hydrochloride (Compound A21) Prepared according to Method A, from 2,4-dichloroquinazoline, 4-tert-butylcyclohexylamine and 3,5-dimethylpyrazole. P.f. 253-255 ° C. [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] - (tetrahydro-pyran-4-yl) -amine hydrochloride (Compound A22) Prepared according to Method A, from 2,4-dichloroquinazoline, 4-aminotetrahydropurane and 3,5-dimethylpyrazole. P.f. 269-272.3 ° C.

Cryohexyl- [2- (3,5-diisopropyl-pyrazol-l-yl) -quinazolin-4-yl] -amine hydrochloride (Compound A23) Prepared according to Method A, from 2,4-dichloroquinazoline , cyclohexylamine and 3,5-diisopropylpyrazole with sodium hydride as a base, instead of triethylamine. P.f. 83.4-85.3 ° C 4-Cyclohexylsulfanyl-2- (3,5-dimethyl-pyrazol-1-yl) -quinazoline hydrochloride (Compound A24) Prepared according to Method A, from 2,4-dichloroquinazoline, cyclohexanilthiol and 3,5-dimethylpyrazole with sodium hydride as a base, instead of triethylamine, Pf 92.7-94.1 ° C. 4-Cyclohexyloxy-2- (3, 5-dimethyl-pyrazol-1-yl) -quinazoline hydrochloride (Compound A25) Prepared according to Method A, from 2,4-dichloroquinazoline, cyclohexanol and 3, 5 -dimethylpyrazole.

P.f. 152.9-153, 5 ° C. [2- (3,5-Dimethyl-pyrazol-l-yl) -quinazolin-4-yl] -indan-2-yl-amine hydrochloride (Compound A26) Prepared according to Method A, from 2 , 4-dichloroquinazoline, 2-aminoindane and 3,5-dimethylpyrazole. P.f. 212-215 ° C. Cryohexyl- (2-pyrazol-l-yl-quinazolin-4-yl) -amine (Compound A27) Prepared in accordance with Method A, starting of 2,4-dichloroquinazoline, cyclohexylamine and pyrazole. CL-ERI-EMAR of [M + H] + showed 294,173 Da. Cale. 294.17187 Da, dev. 3.8 ppm.

Method B [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -phenyl-amine (Compound Bl) 2,4-Dichloroquinazoline (500 mg, 2.5 mmol) was dissolved in acetonitrile ( 3 ml). Aniline (260 mg, 2.76 mmol) and triethylamine (380 mg, 3.75 mmol) were added. The mixture was shaken in a sealed vial and in a sand bath at 60 ° C. 12 hours. Filtration and evaporation of the filtrate provide a yellow solid. Column chromatography (ethyl acetate: hexane), provided (2-chloro-quinazolin-4-yl) -propylamine (350 mg, 55%). (2-Chloro-quinazolin-4-yl) -phenyl amine (250 mg, 0.98) was dissolved in acetonitrile (4 ml) and 3,5-dimethylpyrazole (140 mg, 1.47 mmol) was added. The mixture was heated in a sealed tube at 130 ° C for 12 hours. The mixture was concentrated and the residue was basified with sodium hydrogencarbonate, extracted with chloroform, dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography (ethyl acetate / hexane) to give [2- (3,5-dimethyl-1-pyrazol-1-yl) -quinazolin-4-yl] -phenyl-amine (150 mg, 49%). %). P. f. 262.4-265.3 ° C.

The following compounds were prepared in analogy together with these: (4-Chloro-phenyl) - [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine (Compound B2) was prepared in accordance with Method B, from 2,4-dichloroquinazoline, 4-chloroaniline and 3,5-dimethylpyrazole. P.f. 209.3-211.2 ° C. (3-Chloro-phenyl) - [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine (Compound B3) Prepared according to Method B, from 2 , 4-dichloroquinazoline, 3-chloroaniline and 3,5-dimethylpyrazole. P.f. 259.1-262.4 ° C. (2-Chloro-phenyl) - [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine (Compound B4) Prepared according to Method B, from 2 , 4-dichloroquinazoline, 2-chloroaniline and 3,5-dimethylpyrazole. P.f. 210.4-217.1 ° C. (3,4-Dichloro-phenyl) - [2- (3,5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine (Compound B5) It was prepared according to Method B, starting from of 2,4-dichloroquinazoline, 3,4-di-chloroaniline and 3,5-dimethylpyrazole. P.f. 223.9-226.5 ° C. (4-Bromo-phenyl) - [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine (Compound B6) Prepared according to Method B, starting from of 2,4-dichloroquinazoline, 4-bromoaniline and 3,5-dimethylpyrazole. P.f. 116.2-168.3 ° C. [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] - (4-trifluoromethyl-phenyl) -amine 5 (Compound B7) Prepared according to Method B, starting from 2,4-dichloroquinazoline, 4-trifluoromethylaniline and 3,5-dimethylpyrazole. P.f. 218.8-220.1 ° C. [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] - (3-methoxy-phenyl) -amine (Compound B8) Prepared according to Method B, from 2 , 4-dichloroquinazoline, m-anisidine and 3,5-dimethylpyrazole. P.f. 193.1-194.7 ° C. [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -p-tolyl-amine (Compound B9) Prepared according to Method B, from 2,4-dichloroquinazoline , p-toluidine and 3,5-dimethylpyrazole. P.f.210.4-216.2 ° C. [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -m-tolyl-amine (Compound BIO) Prepared according to Method B, from 2,4-dichloroquinazoline , m-toluidine and 3,5-dimethylpyrazole. P.f. 249.2-250.4 ° C. [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -o-tolyl-amine (Compound Bll) Prepared according to Method B, starting from of 2,4-dichloroquinazoline, o-toluidine and 3,5-dimethylpyrazole. P.f. 240.1 -244.4 ° C. [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -naphthalen-2-yl-amine (Compound B12) Was prepared according to Method B, starting at 2, 4 -dichloroquinazoline, 2-naphthylamine and 3,5-dimethylpyrazole. P.f. 213.3-215.6 ° C. Benzo [1,3] dioxol-5-yl- [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine (Compound B13) Prepared according to Method B, from 2,4-dichloroquinazoline, 3, 4- (methylenedioxy) aniline and 3,5-dimethylpyrazole. CL-ERI-EMAR of [M + H] + showed 360,148 Da. Cale. 360.14605 Da, dev. 5.4 ppm. (3, 5-Bis-trifluoromethyl-phenyl) - [2- (3, 5-dimethyl-1-pyrazol-1-yl) -quinazolin-4-yl] -amine (Compound B14) Prepared according to Method B, from 2,4-dichloroquinazoline, 3,5-bis (trifluoromethylmethyl) aniline and 3,5-dimethylpyrazole. P.f. 169.2-172.4 ° C. [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] - (4-morpholin-4-yl-phenyl) -amine (Compound B15) Prepared according to Method B, from 2,4-dichloroquinazoline, N- (4-aminophenyl) -morpholine and 3,5-dimethylpyrazole. P.f. 268.2-270.4 ° C. [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -quinolin-8-yl-amine (Compound B16) Prepared according to Method B, starting at 2, 4 -dichloroquinazoline, 8-aminoquinoline and 3,5-dimethylpyrazole. P.f. 183, 5-184.8 ° C. [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] - (4-iodo-phenyl) -amine (Compound B17) Prepared according to Method B, from 2 , 4-dichloroquinazoline, 4-iodoaniline and 3,5-dimethylpyrazole. P.f. 226.5-229.1 ° C. Biphenyl-4-yl- [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine (Compound B18) Prepared according to Method B, starting at 2, 4 -dichloroquinazoline, 4-aminobiphenyl and 3,5-dimethylpyrazole. P.f. 267.5-270.3 ° C. 2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] - (3-trifluoromethyl-phenyl) -amine (Compound B19) Prepared according to Method B, starting at 2, 4-dichloroquinazoline, 3- trifluoromethylaniline and 3,5-dimethylpyrazole. P.f. 233.1-239.6 ° C. [2- (3, 5-Dimethyl-1-pyrazol-1-yl) -quinazolin-4-yl] -pyridin-2-yl-amine (Compound B20) Prepared according to Method B, starting at 2, 4 -dichloroquinazoline, 2-aminopyridine and 3,5-dimethylpyrazole. P.f. 126.1-126.8 ° C. [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] - (1H-indol-7-yl) -amine hydrochloride (Compound B21) Prepared according to Method B, from 2,4-dichloroquinazoline, 6-aminoindole and 3,5-dimethylpyrazole. P.f. 298.5-303.4 ° C.

Example 2 Biological Activity This example demonstrates the biological activity of a representative compound of the invention (Compound A8). Ionic current through K + channels activated by Ca 2+ of minor conductance (SK channels, subtype 3), was recorded using full cell centrifugation of the patch clamping technique. The minor conductance Ca2 + activated K + channel, subtype 3 (SK3), was cloned from the human skeletal muscle and expressed stably in HEK293 cells.

Stable Expression of SK3 in HEK293 Cells Human SK3 (hSK3) was subcloned into the expression vector pNS3n, a customary vector derived from pcDNA3 (Invitrogen), to give the plasmid construct pNS3_hSK3. The HEK293 tissue culture cells were grown in DMEM (Dulbeco Modified Eagle Medium), supplemented with 10% FCS (fetal bovine serum) at 37 ° C in C02 at 5%. Cells grown at 50% confluence in a T25 cell culture flask were transfected with 2.5 μg of pNS3_hSK3 using lipofectamine (Invitrogen). The transfected cells were selected in medium supplemented with 0.25 mg / ml Zeocin. Unique clones were chosen and propagated in selection medium until enough cells for freezing are available. Subsequently, the cells were cultured in regular medium without selection agent. The expression of functional hSK3 channels was verified by patch clamping measurements.

Complete Cell Registers Experiments were carried out in one of the several upper sets of fastening patches. Cells plated on coverslips were placed in a 15 μl perfusion chamber (flow rate ~ 1 ml / min), mounted on an IMT-2 microscope. The microscopes were placed on vibration-free tables in Faraday boxes connected to the ground. All the experiments were carried out at room temperature (20-22 ° C). The patch clamp amplifiers EPC-9 (HEKA-electronics, Lambrect, Germany) were connected to Macintosh computers via ITC16 interfaces. The data is stored directly on the hard disk and analyzed by IGOR software (Wavemetrics, Lake Oswega, OR, USA). The full cell configuration of the patch fastening technique. In brief: The tip of the borosilicate pipette (resistance 2-4 MO) is uniformly placed on the cell membrane using remote control systems. The suction of light results in the formation of a giga seal (the resistance of the pipette increases to more than 1 GO) and the cell membrane under the pipette is then broken by more powerful suction. The cellular capacitance is electronically compensated and the resistance between the pipette and the cell interior (series resistors, Rs), is measured and compensated. Usually, the cellular capacitance varies from 5 to 20 pF (depending on the cell size) and the series resistances are in the range of 3 to 6 MO. Rs-as well as capacitance compensation are updated during the experiments (before each stimulus). All experiments with removed Rs values are downloaded. Weak subtractions are not made.

Solutions The extracellular solution (bath) contains (in mM): 140 NaCl, 4 KCl, 0.1 CaCl2, 3 MgCl2, 10 HEPES (pH = 7.4 with HCl). The test compound was then dissolved 1000 times in DSMO from a concentrated base solution and then diluted in the extracellular solution. The intracellular solution (pipette) has the following composition (in mM): 105 KCl, 45 KOH, 10 EGTA, 1.21 MgCl2, 7.63 CaCl2, and 10 HEPES (pH = 7.2 with HCl). The calculated free concentration of Ca2 + in this solution is 300 nM and that of Mg2 + is 1 mM.

Quantification After the establishment of the complete cellular configuration, the voltage ramps (usually -120 to +30 mV) are applied to the cell every 5 seconds from a clamping potential of -80 mV. A stable baseline current is obtained within a period of 100-500 seconds, and the compound is then added by changing to an extracellular solution containing the test compound. Very little endogenous current is activated (< 200 pA at 30 mV, compared to SK3 current of 2-10 nA), under these circumstances in native HEK293 cells. The active compounds are quantified by calculating the change in the baseline current at -20 mV. The current in the absence of a compound is set to 100%. The activators will have values greater than 100, and a value of 200%, indicates a current bend. On the other hand, a value of 50% indicates that the compound has reduced the current of the baseline to half its value. For triggers, an SCioo value can be estimated. The SCioo value is defined as the Stimulation Concentration required to increase the line current base by 100%. The SCioo value determined for Compound A8 of the invention was 0.035 μM, which is an indication of its strong SK3 activation properties. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims

CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. Derivative of pyrazolyl quinazoline characterized in that it is of Formula I: an isomer or a mixture of its isomers, an N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2 or 3; X represents O, S or NR '; wherein R 'represents hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl; or, when n is 0 and X is NR ', R' together with Y and together with the nitrogen to which they are attached form a heterocyclic ring, in which the heterocyclic ring can be optionally substituted with alkyl or phenyl; Y represents an alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxy-alkyl, alkoxyalkyl, alkenyl, or monocyclic or polycyclic, carbocyclic group or heterocyclic, in which the carbocyclic or heterocyclic groups may be optionally substituted one or more times with substituents selected from the group consisting of alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxy-alkyl, alkoxy -alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, nitro, amino, methylenedioxy, phenyl and morpholinyl; or, when n is 0 and X is NR ', Y together with R' and together with the nitrogen to which they are attached, form a heterocyclic ring, in which, the heterocyclic ring can optionally be substituted with alkyl or phenyl; and R1, R2 and R3 independently of each other, represent hydrogen, alkyl, amino-alkyl, alkyl-amino, alkylamino-alkyl, hydroxy-alkyl, alkoxy-alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, halo, haloalkyl, hydroxy , alkoxy, haloalkoxy, alkoxycarbonyl, cyano, nitro and amino.
2. Derivative of pyrazolyl quinazoline according to claim 1, characterized in that n is 0, 1, 2 0 3.
3. Derivative of pyrazolyl quinazoline according to any of claims 1-2, characterized in that X represents O, S or NR '; wherein R 'represents hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl; or, when n is 0 and X is NR '; R 'together with Y and together with the nitrogen to which they are attached form a heterocyclic ring, in which the heterocyclic ring can be optionally substituted with alkyl or phenyl.
4. Derivative of pyrazolyl quinazoline according to claim 1, characterized in that n is 0; X represents NR '; and R 'together with Y and together with the nitrogen to which they are attached form a heterocyclic ring, in which the heterocyclic ring can optionally be substituted with alkyl or phenyl.
A pyrazolyl quinazoline derivative according to any of claims 1-4, characterized in that Y represents an alkyl, amino-alkyl, alkylamino, alkyl-amino-alkyl, hydroxy-alkyl, alkoxy-alkyl, alkenyl or monocyclic group or polycyclic, carbocyclic or heterocyclic, in which the carbocyclic or heterocyclic groups may be optionally substituted one or more times with substituents selected from the group consisting of alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxy alkyl, alkoxy-alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, nitro, amino, methylenedioxy, phenyl, and morpholinyl; or, when n is 0 and X is NR '; And together with R 'and together with the nitrogen to which they are attached, they form a heterocyclic ring, in which, the heterocyclic ring can optionally be substituted with alkyl or phenyl.
6. A pyrazolyl quinazoline derivative according to claim 5, characterized in that Y represents alkyl, alkenyl or cycloalkyl.
A pyrazolyl quinazoline derivative according to claim 5, characterized in that Y represents a monocyclic or carbocyclic polycyclic group, selected from phenyl, naphthyl, or 1,2,3,4-tetrahydro-naphthyl; or a monocyclic or polycyclic heterocyclic group, selected from pyrrolidinyl, piperidinyl, furanyl, thienyl and pyrrolyl; wherein the phenyl, naphthyl, 1, 2, 3, 4-tetrahydro-naphthyl, pyrrolidinyl, piperidinyl, furanyl, thienyl and pyrrolyl groups can be optionally substituted once or twice with substituents selected from the group consisting of alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxy-alkyl, alkoxy-alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, nitro and amino.
8. A pyrazolyl quinazoline derivative according to claim 5, characterized in that Y represents a monocyclic or polycyclic carbocyclic group, selected from phenyl, naphthyl, 1,2,3,4-tetrahydro-naphthyl groups and indanyl, in which the carbocyclic groups may optionally be substituted one or more times with substituents selected from the group consisting of alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxy-alkyl, alkoxy-alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, nitro, amino, methylenedioxy, phenyl and morpholinyl.
9. A pyrazolyl quinazoline derivative according to claim 5, characterized in that Y represents a heterocyclic group, in which the carbocyclic or heterocyclic groups can be optionally substituted one or more times with substituents selected from the group consisting of alkyl, amino-alkyl, alkyl-amino, alkyl-amino-alkyl, hydroxy-alkyl, alkoxy-alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, nitro, amino.
10. A pyrazolyl quinazoline derivative according to any of claims 1-9, characterized in that R1, R2, and R3, independently of each other, represent hydrogen, alkyl, amino-alkyl, alkylamino, alkylamino-alkyl, hydroxy- alkyl, alkoxy-alkyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, alkoxycarbonyl, cyano, nitro and amino.
11. A pyrazolyl quinazoline derivative according to claim 10, characterized in that R1 and R2 independently of one another represent hydrogen or alkyl; and R3 represents hydrogen.
12. A pyrazolyl quinazoline derivative according to claim 1, characterized in that n is 0; X represents O, S or NR '; wherein R 'represents hydrogen, methyl, ethyl or propyl; Y represents alkyl, alkenyl, cycloalkyl, alkyl-cycloalkyl; and R1 and R2 represent methyl or isopropyl; and R3 represents hydrogen.
13. Derivative of pyrazolyl quinazoline according to claim 1, characterized in that n is 0 or 1; X represents NH; Y represents phenyl, optionally substituted once or twice with substituents selected from the group consisting of alkyl, halo, haloalkyl, alkoxy, methylenedioxy, phenyl and morpholinyl; R1 and R2 represent methyl or isopropyl; and R3 represents hydrogen.
14. Derivative of pyrazolyl quinazoline from according to claim 1, characterized in that n is 0; X represents NR '; and R 'together with Y and together with the nitrogen to which they are attached, form a pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring; and R1 and R2 independently from each other, represent methyl, ethyl or propyl; and R3 represents hydrogen.
15. Pyrazole quinazoline derivative according to claim 1, characterized in that it is: [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -propylamine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -ethylamine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -diethyl-amine; Butyl- [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; Allyl- [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; Cyclopropyl- [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; Cyclopentyl- [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; Cyclohexyl- [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; Cycloheptyl- [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; Cyclooctyl- [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; 2- (3, 5-Dimethyl-pyrazol-1-yl) -4-piperidin-1-yl-quinazoline; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -piperidin-4-yl-amine; Benzyl- [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; (4-Chloro-benzyl) - [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; (3,4-Difluoro-benzyl) - [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -furan-2-ylmethyl-amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -thiophen-2-ylmethyl-amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -phenyl-amine; (4-Chloro-phenyl) - [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; (3-Chloro-phenyl) - [2- (3,5-dimethyl-pyrazol-1-yl) - quinazolin-4-yl] -amine; (2-Chloro-phenyl) - [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; (3,4-Dichloro-phenyl) - [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; (4-Bromo-phenyl) - [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] - (4-trifluoromethyl-phenyl) -amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] - (3-trifluoromethyl-phenyl) -amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] - (3-methoxy-phenyl) -amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -p-tolyl-amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -m-tolyl-amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -o-tolyl-amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -naphthalen-2-yl-amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] - (1,2,3,4-tetrahydro-naphthalen-1-yl) -amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] - (2-pyrrolidin-1-yl-ethyl) -amine; Cyclohexyl- [2- (3-methyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; S- [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] - (S) -1,2,3,4-tetrahydro-naphthalene-1-yl-amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] - (1-ethyl-propyl) -amine; [2- (3,5-Diisopropyl-pyrazol-1-yl) -quinazolin-4-yl] - (4-methyl-cyclohexyl) -amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -pyridin-2-yl-amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] - (4-methyl-cyclohexyl) -amine; (4-tert-Butyl-cyclohexyl) - [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] - (tetrahydro-pyran-4-yl) -amine; Cicyclohexyl- [2- (3, 5-diisopropyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -indan-2-yl-amine; Benzo [1,3] dioxol-5-yl- [2- (3, 5-dimethyl-1-pyrazol-1-yl) -quinazolin-4-yl] -amine; (3,5-Bis-trifluoromethyl-phenyl) - [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] - (4- morpholin-4-yl-phenyl) -amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -quinolin-8-yl-amine; [2- (3, 5-Dimethyl-pyrazol-1-yl) -quinazolin-4-yl] - (4-iodo-phenyl) -amine; Biphenyl-4-yl- [2- (3, 5-dimethyl-pyrazol-1-yl) -quinazolin-4-yl] -amine; [2- (3, 5-Dimethyl-pyrazol-l-yl) -quinazolin-4-yl] - (1-H-indol-7-yl) -amine; or Cicyclohexyl- (2-pyrazol-l-yl-quinazolin-4-yl) -amine; or a pharmaceutically acceptable salt thereof.
16. A pharmaceutical composition characterized in that it comprises a therapeutically effective amount of a pyrazolyl quinazoline derivative according to any of claims 1-15, or a pharmaceutically acceptable addition salt thereof, or a prodrug thereof, together with at least one , a pharmaceutically acceptable carrier or diluent.
17. Use of a pyrazolyl quinazoline derivative according to any of claims 1-15, for the manufacture of a medicament for the treatment, prevention or alleviation of a disease or disorder or condition of a mammal, including a human, in which the disease, disorder or condition is associated with the activity of potassium channels.
18. Use according to claim 17, wherein the disease or a disorder associated with the activity of potassium channels is a disorder associated with the activity of potassium channels is a respiratory disease, epilepsy, seizures, seizures, absence attacks, spasms vascular diseases, coronary artery spasms, renal disorders, polycystic kidney disease, bladder spasms, urinary incontinence, bladder flow obstruction, erectile dysfunction, gastrointestinal dysfunction, secretory diarrhea, ischemia, cerebral ischemia, ischemic heart disease, angina pectoris, disease coronary heart disease, ataxia, traumatic brain injury, Parkinson's disease, bipolar disorder, psychosis, schizophrenia, anxiety, depression, mood disorders, dementia, attention deficit and memory, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), dysmenorrhea, narcolepsy, Reynaud's disease, intermittent claudication, Sjorgren's syndrome, arrhythmia, hypertension, myotonic muscular dystrophy, spasticity, xerostomia, type II diabetes, hyperinsulinemia, preterm labor, baldness, cancer, irritable bowel syndrome, immune suppression, migraine or pain.
19. Use according to claim 17, wherein the disease or a disorder associated with the activity of potassium channels, is a respiratory disease, urinary incontinence, erectile dysfunction, anxiety, epilepsy, psychosis, schizophrenia, amyotrophic lateral sclerosis (ALS) or pain.
20. Use according to claim 17, wherein the activity of potassium channels is a respiratory disease, in particular, asthma, cystic fibrosis, chronic obstructive pulmonary disease (COPD) or rhinorrhea.
21. Method of treatment, prevention or alleviation of a disease or disorder of a condition of a living animal body, including a human, characterized in that the disease, disorder or condition is receptive to the modulation of the potassium channels, and wherein, the method comprises administering to such a living animal body, including a human in need of a therapeutically effective amount thereof, a pyrazolyl quinazoline derivative according to any of claims 1-15.